A collaborative landmark study has been conducted to show that long-term exposure to outdoor PM2.5 is associated with excess cardiovascular disease (CVD) mortality, including ischemic heart disease (IHD). Because a large percentage of the U.S. population is affected by substantial levels of PM2.5 and CVD is a leading cause of death, the impact of air pollution on CVD represents a serious public health problem. One of the leading hypotheses for these air pollution effects is via oxidative stress on the circulatory system. Obesity, lower intake of fruits and vegetables, and higher intake of alcohol and saturated fat provide greater oxidative stress burden, and these dietary factors are also well established risk factors for CVD. Thus, the hypothesis is that the adverse effects of PM2.5 air pollution on CVD mortality is modified by these dietary factors. This hypothesis will be tested in the NIH-AARP Diet and Health Study, the largest cohort of US adults (N=537,694), with up to 13 years prospective follow-up for mortality (including 27,360 CVD deaths and 15,941 IHD deaths). As a central part of the NIH-AARP Diet and Health Study, detailed food and nutrient intakes and anthropometry were assessed with a validated food frequency questionnaire and self-measurements, respectively. This unique individual-level cohort information will be linked with estimated ambient air pollution exposure, derived from nationwide air pollution monitoring data from the EPA Air Quality System and the PM2.5 Chemical Speciation Network databases. Time-dependent ambient air pollution exposure estimates (PM2.5 mass and PM2.5 constituents) will be developed during follow-up for each cohort participant. The concept that exposure to outdoor air pollution (especially PM2.5 and its chemical constituents) is associated with risk of CVD and IHD mortality, and that the relationship between outdoor air pollution exposure and risk of CVD/IHD mortality differs according to adiposity and intake of fruits and vegetables, antioxidant nutrients, alcohol, and saturated fat will be examined. This study seeks to identify diet-related sub-populations most susceptible to the effects of PM2.5 on CVD risk, providing knowledge for the development of national particulate matter air quality standards that most appropriately protect the health of the U.S. population. It will also provide directly applicable information to individuals and their physicians for tailored guidance for modification of individua diet-related susceptibility to PM2.5 risks. Given continuing air pollution-related CVD mortality in the US, the common frequency of unhealthy diets, and the increasing obesity epidemic, there is a significant need for this investigation. PUBLIC HEALTH RELEVANCE: The effect of PM2.5 (the mass concentration of particles less than 2.5 m in aerodynamic diameter) in ambient air on cardiovascular disease mortality is a significant public health burden that has been identified by the American Heart Association as a modifiable cardiac risk. We will test whether intake of fruit and vegetable and antioxidant nutrients or obesity modify the adverse effect of PM2.5 on cardiovascular mortality in the NIH- AARP Diet and Health cohort, comprising over one-half million subjects. This research will thereby enable the development of more effective primary prevention and intervention strategies to mitigate environmentally- induced disease from air pollution exposures.